Osteoarthritis (OA) is the most common form of arthritis and disease in the knee is a leading cause of disability. Most epidemiologic studies of knee OA have focused on radiographic disease, but symptomatic OA should be a major focus of studies on preventing OA, because symptomatic disease causes disability and has formidable societal and public health impacts. OA is potentially preventable, but only a limited number of mostly nonmodifiable risk factors has been identified, even though modifiable risk factors such as particular activities, muscle weakness, proprioceptive deficits, micronutrient deficiencies and structural factors have been proposed and may affect substantially the risk of disease. Prevention opportunities are most relevant and are most likely to be used by those who already have disease or who are at highest risk of getting it. This proposal introduces four new approaches into the epidemiologic study of knee osteoarthritis: l.a focus on symptomatic disease, 2. a comprehensive evaluation of risk factors including modifiable ones, 3. a focus on those who would really benefit from prevention opportunities, those who already have disease or those who are at high risk of getting it and 4. the incorporation of more comprehensive and reproducible imaging than has previously been used including, state of the art radiographic techniques and MRI. MRI provides rich information on structural factors in which abnormalities may affect the risk of disease. The overall objective of this study is to evaluate longitudinally the effects of three groups of factors: biomechanical factors (squatting,kneeling, stair climbing, quadriceps weakness and proprioceptive deficits), bone and structural factors (bone density,bone marrow and meniscal lesions on MRI) and micronutrient deficiencies (vitamin C, E and D) on the occurrence and progression of symptomatic and radiographic knee OA in a population-based sample of men and women aged 50 to 79. We propose to recruit a community-based sample of 3,000 men and women likely to either have knee OA or be at high risk of OA. High risk groups will include those who are overweight, those with knee symptoms or those with a history of knee injuries or operations. Subjects will be evaluated with symptom questionnaires, radiographs and MRI's and will be followed 36 months for the development or progression of symptomatic or radiographic OA. Analyses will focus on the relation of these important risk factors and OA outcomes. This large, multifaceted and comprehensive study of persons with knee OA, or at high risk of disease, offers to address definitively the relation of potentially important risk factors to the development or progression of a major disabling disease and to provide new insights into disease biology and potential opportunities for prevention. Boston University Medical Campus 715 Albany Street, Rm. A203 Boston, Massachusetts 02118 KEY PERSONNEL. See instructions on Page 11. Use continuation pages as information in the format shown below. Name Organization David T. Felson, MD, MPH^ Boston University School of Medicine Michael LaValley, PhD^ Boston University School of Medicine Yuqing Zhang, DSc * Boston University School of Medicine Paul Jacques, ScD )\ USDA Human Nutrition Center on Aging Piran Aliabadi, MD ^ Brigham & Womens Hosp., Boston, MA Leena Sharma, MD ^ Northwestern University, Chicago, Illinois Burton Sack, MD A . Boston University School of Medicine Michael Hurley, PhD^ King's College, London, England Casey Kerrigan, MD X Spaulding Rehabilitation Hospital, Harvard Medical School needed to provide the required Role on Project Principal Investigator Co-Investigator Co-Investigator Co-Investigator, Subcontract PI Consultant Consultant Consultant Consultant Consultant PHS 398 (Rev. 4/98) (Format Page 8) Page! 2 l_ HH cc Principal Inv^^ator/Program Director (Last, first, middle): Felsc ivid T. Type the name of the principal investigator/program director at the top of each printed page and each continuation page. (For type specifications, see instructions on page 6.) RESEARCH GRANT TABLE OF CONTENTS Page Numbers Face Page 1 Description,